Human susceptibility to infection by pathogens is affected by variations in an important regulator of a protein that is pivotal to stimulating the immune response, according to an international team of molecular biologists led by Chiea Chuen Khor of the A*STAR Genome Institute of Singapore (GIS). The work represents a first step toward new therapies to strengthen the immune system against multiple and diverse infections.
Previous studies have shown that individual susceptibility to disease depends not only on obvious environmental factors, such as the state of nutrition and general health, but also on underlying genetic factors. Until now, however, with the exception of mutations directly impacting the immune system, there has been limited research on the general genetic environment affecting susceptibility to infectious disease.
A principal weapon against infectious disease is the inflammatory cytokine response, a chain of biochemical signals that determines the magnitude and duration of the immune response. The response is stimulated by the production and release of interleukin-2. The inflammatory response must be carefully targeted and controlled because, in excess, it can be as harmful as the infections it counters.
The team’s work focused on CISH gene variants that are carried by a significant proportion of the human population—more than one third of Southeast Asians, for instance. This gene is stimulated by interleukin-2 and is responsible for the production of CISH, a negative regulator of interleukin-2 and its interactions.
To test whether variants of the CISH gene may influence the gene’s ability to act on interleukin-2, and hence affect human susceptibility to common infectious diseases, Khor and his co-workers analyzed blood-sample data from about 8,400 people in Gambia, Hong Kong, Kenya, Malawi and Vietnam. They tested the association between five mutations, called nucleotide polymorphisms (SNPs), in CISH and susceptibility to bacterial infection, tuberculosis and severe malaria.
They found that people carrying any one of these SNPs are about 18% more susceptible to infectious disease, and that the increased risk is additive, rising to about 81% for those with four or more of the CISH SNPs. “This is the first time a controller of immune signaling has been implicated in human susceptibility to infection,” Khor says.
“Under the leadership of Martin Hibberd of the GIS, we are currently undertaking large-scale genome-wide association studies on a variety of other infectious diseases involving multiple field sites,” explains Khor. “The plan is to identify culprit genes which modify human susceptibility to infections, thus providing potential targets for pharmacological or immunological manipulation in the future.”